PROJECT SUMMARY Microbiota in animals provides an important barrier to infection against diverse microbial pathogens and encode an important reservoir of anti-infective and protective factors. To identify anti-infective and protective factors from beneficial bacterial species in gut microbiota, we used C. elegans as a model organism to evaluate individual bacteria species and specific factors for protective activity against human enteric pathogens such as Salmonella typhimurium. We discovered that a unique secreted peptidoglycan hydrolase, SagA, from Enteroccocus faecium (commensal bacteria in humans and other animals) enhanced epithelial barrier function and was sufficient to protect C. elegans and mice from S. typhimurium pathogenesis. These exciting results suggest that SagA has unique activity in vivo and may be used to improve host barrier function to protect against enteric pathogens and inflammatory bowl diseases (IBDs) in humans. To harness the protective activity of SagA for therapeutic use, we propose to determine the precise mechanism(s) of SagA-mediated protection in mammalian cells and mouse models. Our discovery of SagA protective activity provides an exciting opportunity to understand the protective mechanism of beneficial gut bacterial species such as E. faecium and to prevent or treat enteric microbial infections as well as inflammatory bowl disorders.